Tablet composition

ABSTRACT

A tablet composition containing N-(trans-4-isopropylcyclobexanecarbonyl)-D-phenylalanine and low sustituted hydxoxypropylcellulose is disclosed. This tablet composition is rapidly disintegrated in the stomach after the administration and absorbed without being influenced by meals to inhibit the rise of the blood sugar levels of diabetics after meals.

TECHNICAL FIELD

[0001] The present invention relates to a tablet composition used forcontrolling the blood sugar levels of diabetics.

BACKGROUND OF THE INVENTION

[0002] It is known thatN-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine of thefollowing formula:

[0003] (hereinafter referred to as “compound [1]) exhibits an excellenteffect of lowering the blood sugar level when it is taken orally, and isthus usable as a medicine for diabetes [Japanese Patent Publication forOpposition Purpose (hereinafter referred to as “J. P. KOKOKU”) No. Hei4-15221].

[0004] However, it was found that when compound [1] is orally takenbefore or after a meal for the purpose of preventing the blood sugarlevel after the meal from rising, the bioavailability of the compound islowered.

DISCLOSURE OF THE INVENTION

[0005] The object of the present invention is to provide a tabletcomposition which is rapidly absorbed without being influenced by themeals and without impairing the essential properties of compound [1]contained therein, which has an effect of lowering the blood sugar leveland only a short effect-lasting time.

[0006] The present invention relates to a tablet composition containingcompound [1] as the active ingredient and a low sustitutedhydroxypropylcellulose as a disintegrator.

[0007] The present invention also relates to a tablet compositioncontaining a filler, preferably a filler containing lactose, in additionto said compound [1] and the low sustituted hydroxypropylcellulose.

[0008] The present invention further relates to the above-describedtablet composition which further contains a hydroxypropyl cellulose as abinder.

[0009] After the administration, the above-described tablet compositionsare rapidly disintegrated in the stomach after the administration andabsorbed without being influenced by the meals to prevent the bloodsugar level of diabetics after meals from rising.

BRIEF DESCRIPTION OF DRAWINGS

[0010]FIG. 1 shows the concentration of compound [1] in the blood plasmaof patients fasting from foods.

[0011]FIG. 2 shows the concentration of compound [1] in the blood plasmaof patients, which was administered before meals.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] The active compound in the tablet composition of the presentinvention is N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine[compound 1] of the above formula. Processes for producing compound [1]are described in J. P. KOKOKU No. Hei 4-15221 or the like. This compoundcan be obtained by, for example condensing4-isopropylcyclohexanecarboxylic acid with D-phenylalanine or an esterthereof by, for example, active ester method. Processes for obtainingstable crystals of this compound are described in Japanese PatentUnexamined Published Application (hereinafter referred to as “J. P.KOKAI”) No. Hei 5-208943. For example, compound [1] can be obtained bycrystallizing from a mixed solvent of ethanol, acetone or the like andwater at a temperature of not lower than 10° C.

[0013] The amount of compound [1] in the tablet composition of thepresent invention is usually 5 to 50% by weight, preferably 10 to 40% byweight, and more preferably 20 to 30% by weight.

[0014] The low sustituted hydihoxypropylcellulose contained as adisintegrator in the tablet composition of the present invention is ahydroxypropyl ether of cellulose obtained by esterifying only a part ofhydroxyl groups of pyranose ring of a cellulose with propylene oxide.When dried low sustituted hydroxypropylcellulose is determined, thehydroxypropyl group content thereof is 5.0 to 16.0% by weight (refer tothe Japanese Pharmacopeia, 13^(th) Revision, D-885 to D-888 and U.S.Pharmacopeia, 23^(rd) Revision, pages 2253 to 2254). Examples of the lowsustituted hydchoxypropylcellulose include low substitutedhydroxypropylcellulose L-HPC (LH-11, LH-20, LH-21, LH-22, LH-30, LH-31and LH-32; products of Shin-Etsu Chemical Co., Ltd.).

[0015] The amount of the low sustituted hydroxypropylcellulose isusually 5 to 50% by weight, preferably 5 to 40% by weight, morepreferably 10 to 40% by weight, and most preferably 20 to 40% by weight.

[0016] Sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,sodium croscarmellose sodium, etc. are not preferred because they arecolored during the storage. Although corn starch, sodium carboxymethylstarch, crystalline cellulose, partly pregelatinized starch, etc. havinga low disintegrating property is not preferably used alone, but thedisintegrating property thereof is improved by combining each of themwith low sustituted hydroxypropylcellulose.

[0017] The tablet composition of the present invention can furthercontain lactose, starch, crystalline cellulose, calcium monohydrogenphosphate, light anhydrous silicic acid, titanium oxide, magnesiumaluminometasilicate as the filler, in addition to the above-describedindispensable ingredients. Among them, lactose is preferred because itis not easily incompatible with compound [1]. The amount of the fillercan be the balance in the tablet composition. It is preferably 10 to 90%by weight, more preferably 20 to 80% by weight and more preferably 30 to60% by weight.

[0018] Further, it is desirable to incorporate 0.1 to 5% by weight,preferably 0.5 to 2% by weight, of hydloxypropyl cellulose as a binderso as to facilitate the granulation in the manufacturing process.Hydroxypropyl cellulose used for this purpose is different from theabove-described low sustituted hydroxypropylcellulose. The quantity ofhydroxypropoxyl group in dry hydroxypropyl cellulose is determined to be53.4 to 77.5% by weight (refer to the Japanese Pharmacopeia, 13^(th)Revision, D-880 to D-885 and U.S. Pharmacopeia, 23^(rd) Revision, page2253). Such hydroxypropyl cellulose is easily available as HPC-L, L(fine powder) or the like (products of Nippon Soda Co., Ltd.).

[0019] The tablet composition of the present invention can containadditives usually incorporated into tablet compositions in addition tothe above-described ingredients so far as the effect of the presentinvention is not impaired. The additives include fillers such ascrystalline cellulose, calcium monohydrogen phosphate, starch, lightanhydrous silicic acid, titanium oxide, magnesium aluminometasilicateand polyethylene glycol; disintegrators such as starch, crystallinecellulose, hydroxypropyl starch and partly pregelatinized starch;binders such as gelatin, acacia, ethyl cellulose and polyvinyl alcohol;lubricants such as stearic acid, magnesium stearate, calcium stearate,talk and hydrogenated oil; coating agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose,hydroxypropylmethyl cellulose phthalate, polyvinylacetaldiethylaminoacetate, aminoalkyl methacrylate copolymers and polyvinylacetate phthalate; colorants such as tar colorant and titanium oxide;corrigents such as citric acid, adipic acid, ascorbic acid and menthol;and surfactants such as glycerol monostearate, polysorbates, sodiumlaurylsulfate and sucross esters of fatty acids.

[0020] The tablet composition of the present invention can be preparedby an ordinary wet granulation method, wherein the above-describedingredients are thoroughly mixed and then granulated with water whichmay contain a lower alcohol such as ethanol or isopropanol, the granulesthus obtained are dried and, if necessary, reduced in size and tabletedwith a tableting machine. The tablets thus obtained can be coated, ifdesired.

[0021] The following Examples will further illustrate the presentinvention.

EXAMPLE 1

[0022] The ingredients shown in Table 1 were weighed, and all theingredients excluding magnesium stearate were mixed with a highshearmixer for 10 minutes. Purified water in such an amount (15 to 75 partsby weight) that granules having a diameter of 100 to 500 μm would beobtained was added thereto, and the resultant mixture was granulatedwith a highshear mixer for 10 minutes. The thus-obtained granules werereduced in size with a mill and then dried. Magnesium stearate was addedto the dry granules thus obtained, and the thus-obtained mixture wasblended with a V-shaped blender for 2 minutes and tableted to obtaintablets having a diameter of 7 mm, thickness of 3 mm and weight of 100mg. The disintegration time of the thus-obtained tablets in water wasdetermined according to a disintegration test of the JapanesePharmacopeia. L-HPC(LH-31) (a product of Shin-Etsu Chemical Co., Ltd.)having a hydroxypropoxyl group content of 10 to 12.9% by weight and anaverage particle diameter of not larger than 30 μm was used as the lowsustituted hydchoxypropylcellulose. The results are shown in Table 1.TABLE 1 Composition of the present Comparative +UZ,24/39 compositioninvention 1 2 3 4 5 6 7 8 9 10 Compound [1] 25 25 25 25 25 25 25 25 2525 Lactose 74 49 44 54 64 54 44 44 34 44 Corn starch 20 10 20 10 Nacarboxy- 10 10 methyl starch Partly 10 10 pregelatinized starchCrystalline 5 20 10 10 10 cellulose Low substituted 20 10 20 10 20hydroxypropyl- cellulose Magnesium 1 1 1 1 1 1 1 1 1 1 stearateDisintegration >30 >30 >30 >30 11 0.8 3.1 3.1 3.0 3.8 time (min)

[0023] It is apparent from Table 1 that tablets prepared by using asustituted hydroxypropylcellulose as the disintegrator weredisintegrated more rapidly than tablets prepared by using anotherdisintegrator.

EXAMPLE 2

[0024] 250 g of compound [1], 530 g of lactose and 200 g of lowsustituted hydroxypropylcellulose (LH-31; a product of Shin-EtsuChemical Co., Ltd.) having a hydroxypropoxyl group content of 10.0 to13.0% by weight and an average particle diameter of not larger than 30μm were thoroughly mixed with a highshear mixer. 10 g of hydroxypropylcellulose (HPC-L; a product of Nippon Soda Co., Ltd.) dissolved in 500 gof purified water was added thereto and the obtained mixture wasgranulated with a highshear mixer. The granules thus obtained werereduced in size and dried. 10 g of magnesium stearate was added to thepowder and the thus-obtained mixture was tableted to obtain tabletshaving a diameter of 7 mm, thickness of 3.7 mm and weight of 120 mg andcontaining 30 mg of compound [1]. The tablets were spray-coated with acoating liquid comprising 8 g of hydroxypropylmethyl cellulose, 1.5 g ofpolyethylene glycol 6000, 2.4 g of talc, 0.5 g of titanium oxide and87.6 g of purified water to obtain the coated tablets.

COMPARATIVE EXAMPLE 1

[0025] 250 g of compound [1], 440 g of lactose, 100 g of corn starch and200 g of crystalline cellulose were thoroughly mixed with a highshearmixer. 3.0 g of hydroxypropyl cellulose (HPC-L; a product of Nippon SodaCo., Ltd.) dissolved in 360 g of purified water was added thereto andthe obtained mixture was granulated with a highshear mixer. The granulesthus obtained were reduced in size and dried. 10 g of magnesium stearatewas added to the powder and the obtained mixture was tableted to obtaintablets having a diameter of 7 mm, thickness of 3.7 mm and weight of 120mg and containing 30 mg of compound [1]. The tablets were spray-coatedwith a coating liquid comprising 8 g of hydroxypropylmethyl cellulose,1.5 g of polyethylene glycol 6000, 2.4 g of talc, 0.5 g of titaniumoxide and 87.6 g of purified water to obtain the coated tablets.

[0026] The influences of foods on the oral absorption of the tabletsobtained in Example 2 and Comparative Example 1 were examined. As thecontrols, No. 3 hard gelatin capsules each containing 30 mg of compound[1] and 70 mg of lactose were used. The tablets or capsules were orallyadministered to beagles (n=8), and foods were given five minutes after.Blood samples were taken 0, 15, 30, 45, 60, 90, 120, 180, 240, 360 and480 minutes after the administration and the concentration of compound[1] in the blood plasma was determined by HPLC. The time for attainingthe maximum blood concentration (Tmax), the maximum blood concentration(Cmax) and the area under the curve of the blood concentration (AUC)were determined. For comparison, the same tests were repeated exceptthat the tablets or capsules, were administered to the fasting beagles.The results are shown in Table 2 and FIGS. 1 and 2. TABLE 2 Cmax TmaxAUC (μg/ml) (min) (μg · min/ml) Tablets of Ex. 2 Before meal 6.6 ± 3.368 ± 30 1218 ± 278 Fasting 9.7 ± 2.6 47 ± 36 1635 ± 526 Tablets of Comp.Ex. 1 Before meal 3.5 ± 0.9 131 ± 96  1018 ± 200 Fasting 7.5 ± 3.3 64 ±41 1462 ± 542 Capsules Before meal 3.1 ± 1.1 226 ± 145  738 ± 210Fasting 9.5 ± 2.3 38 ± 36 1445 ± 453

[0027] It is apparent from Table 2 and FIG. 1 that when the tabletcomposition of the present invention was administered to the fastingbeagles, the absorption thereof was equivalent to, or slightly superiorto that of the tablet composition and capsules of Comparative Example 1.On the contrary, when the tablet composition of the present inventionwas administered before meals on the assumption that it is practicallyused in that way, it was rapidly absorbed without being influenced byfoods and it could inhibit the rise of the blood sugar level ofdiabetics after meals, while when the tablet composition or capsules ofComparative Example 1 were used in Comparative Example 1, the absorptionof compound [1] was low and impractical.

EXAMPLE 3

[0028] 330 g of compound [1], 450 g of lactose and 200 g of a lowsustituted hydroxypropylcellulose (LH-31; a product of Shin-EtsuChemical Co., Ltd.) were thoroughly mixed with a highshear mixer. 10 gof hydroxypropyl cellulose (HPC-L; a product of Nippon Soda Co., Ltd.)dissolved in 500 g of purified water was added thereto and the obtainedmixture was granulated with a highshear mixer. The granules thusobtained were reduced in size and dried. 10 g of magnesium stearate wasadded to the powder and the obtained mixture was tableted to obtaintablets having a diameter of 7 mm, thickness of 3.7 mm and weight of 121mg and containing 40 mg of compound [1]. The tablets were spray-coatedwith a coating liquid comprising 8 g of hydroxypropylmethyl cellulose,1.5 g of polyethylene glycol 6000, 2.4 g of talc, 0.5 g of titaniumoxide and 87.6 g of purified water to obtain the coated tablets.

[0029] The influences of foods on the oral absorption of the coatedtablets obtained as described above were examined. The coated tabletshad an absorption superior to that of the tablets or capsules ofComparative Example 1, like the coated tablets of Example 2, when theywere administered during the fasting or before meals. In particular, thecoated tablets could inhibit the rise of the blood sugar level ofdiabetics after meals,

EXAMPLE 4

[0030] 125 g of compound [1], 655 g of lactose and 200 g of lowsubstituted hydroxypropylcellulose (LH-31; a product of Shin-EtsuChemical Co., Ltd.) were thoroughly mixed with a highshear mixer. 10 gof hydroxypropyl cellulose (HPC-L; a product of Nippon Soda Co., Ltd.)dissolved in 500 g of purified water was added thereto and the obtainedmixture was granulated with a highshear mixer. The granules thusobtained were reduced in size and dried. 10 g of magnesium stearate wasadded to the powder and the obtained mixture was tableted to obtaintablets having a diameter of 7 mm, thickness of 3.7 mm and weight of 120mg and containing 15 mg of compound [1]. The tablets were spray-coatedwith a coating liquid comprising 8 g of hydroxypropylmethyl cellulose,1.5 g of polyethylene glycol 6000, 2.4 g of talc, 0.5 g of titaniumoxide and 87.6 g of purified water to obtain the coated tablets.

[0031] The influences of foods on the oral absorption of the coatedtablets obtained as described above were examined. The coated tabletshad an absorption superior to that of the tablets or capsules ofComparative Example 1, like the coated tablets of Example 2, when theywere administered during the fasting or before meals. In particular, thecoated tablets could inhibit the rise of the blood sugar level ofdiabetics after meals,

EXAMPLE 5

[0032] 250 g of compound [1], 430 g of lactose, 100 g of crystallinecellulose and 200 g of low substituted hydroxypropylcellulose (LH-31; aproduct of Shin-Etsu Chemical Co., Ltd.) were thoroughly mixed with ahighshear mixer. 10 g of hydroxypropyl cellulose (HPC-L; a product ofNippon Soda Co., Ltd.) dissolved in 570 g of purified water was addedthereto and the obtained mixture was granulated with a highshear mixer.The granules thus obtained were reduced in size and dried. 10 g ofmagnesium stearate was added to the powder and the obtained mixture wastableted to obtain tablets having a diameter of 7 mm, thickness of 3.7mm and weight of 120 mg and containing 30 mg of compound [1]. Thetablets were spray-coated with a coating liquid comprising 8 g ofhydroxypropylmethyl cellulose, 1.5 g of polyethylene glycol 6000, 2.4 gof talc, 0.5 g of titanium oxide and 87.6 g of purified water to obtainthe coated tablets.

[0033] The influences of foods on the oral absorption of the coatedtablets obtained as described above were examined. The coated tabletshad an absorption superior to that of the tablets or capsules ofComparative Example 1, like the coated tablets of Example 2, when theywere administered during the fasting or before meals. In particular, thecoated tablets could inhibit the rise of the blood sugar level ofdiabetics after meals,

EXAMPLE 6

[0034] 250 g of compound [1], 320 g of lactose, 100 g of corn starch,100 g of crystalline cellulose, 100 g of partly pregelatinized starchand 100 g of hydroxypropyl cellulose (LH-31; a product of Shin-EtsuChemical Co., Ltd.) were thoroughly mixed with a highshear mixer. 10 gof hydroxypropyl cellulose (HPC-L; a product of Nippon Soda Co., Ltd.)dissolved in 450 g of purified water was added thereto and the obtainedmixture was granulated with a highshear mixer. The granules thusobtained were reduced in size and dried. 10 g of magnesium stearate wasadded to the powder and the obtained mixture was tableted to obtaintablets having a diameter of 7 mm, thickness of 3.7 mm and weight of 100mg and containing 30 mg of compound [1]. The tablets were spray-coatedwith a coating liquid comprising 8 g of hydroxypropylmethyl cellulose,1.5 g of polyethylene glycol 6000, 2.4 g of talc, 0.5 g of titaniumoxide and 87.6 g of purified water to obtain the coated tablets.

[0035] The influences of foods on the oral absorption of the coatedtablets obtained as described above were examined. The coated tabletshad an absorption superior to that of the tablets or capsules ofComparative Example 1, like the coated tablets of Example 2, when theywere administered during the fasting or before meals. In particular, thecoated tablets could inhibit the rise of the blood sugar level ofdiabetics after meals,

EXAMPLE 7

[0036] 250 g of compound [1], 430 g of lactose, 100 g of sodiumcarboxymethyl starch and 200 g of low substituted hydroxypropylcellulose(LH-31; a product of Shin-Etsu Chemical Co., Ltd.) were thoroughly mixedwith a highshear mixer. 10 g of hydroxypropyl cellulose (HPC-L; aproduct of Nippon Soda Co., Ltd.) dissolved in 640 g of purified waterwas added thereto and the obtained mixture was granulated with ahighshear mixer. The granules thus obtained were reduced in size anddried. 10 g of magnesium stearate was added to the powder and theobtained mixture was tableted to obtain tablets having a diameter of 7mm, thickness of 3.7 mm and weight of 120 mg and containing 30 mg ofcompound [1]. The tablets were spray-coated with a coating liquidcomprising 8 g of hydroxypropylmethyl cellulose, 1.5 g of polyethyleneglycol 6000, 2.4 g of talc, 0.5 g of titanium oxide and 87.6 g ofpurified water to obtain the coated tablets.

[0037] The influences of foods on the oral absorption of the coatedtablets obtained as described above were examined. The coated tabletshad an absorption superior to that of the tablets or capsules ofComparative Example 1, like the coated tablets of Example 2, when theywere administered during the fasting or before meals. In particular, thecoated tablets could inhibit the rise of the blood sugar level ofdiabetics after meals,

[0038] As described above in detail, the tablet composition ofN-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine which israpidly absorbed to exhibit the effect of lowering the blood sugar levelwithout being influenced by meals can be provided by the presentinvention.

What is claimed is:
 1. A tablet composition containingN-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine and lowsustituted hydroxypropylcellulose.
 2. The tablet composition accordingto claim 1, wherein an amount of the low sustitutedhydchoxypropylcellulose contained therein is 5 to 50% by weight.
 3. Thetablet composition according to claim 1, which further contains afiller.
 4. The tablet composition according to claim 3, wherein at leastone kind of the filler is lactose.
 5. The tablet composition accordingto claim 1, which further contains hydroxypropyl cellulose.
 6. Thetablet composition according to claim 5, wherein the hydroxypropylcellulose contains 53.4 to 77.5% by weight of hydioxypropoxyl group. 7.A tablet composition containing 5 to 50% by weight ofN-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine, 5 to 40% byweight of low sustituted hydroxypropylcellulose and 10 to 90% by weightof a filler.
 8. The tablet composition according to claim 7, wherein thefiller is lactose.
 9. The tablet composition according to claim 7, whichfurther contains hydroxypropyl cellulose.
 10. The tablet compositionaccording to claim 9, wherein the hydroxypropyl cellulose contains 53.4to 77.5% by weight of hydroxypropoxyl group.
 11. A tablet compositioncontaining 5 to 50% by weight ofN-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine, 5 to 40% byweight of low sustituted hydroxypropylcellulose having a hydroxypropylgroup content of 5.0 to 16.0% by weight, 10 to 90% by weight of a fillerand 0.1 to 5% by weight of hydioxypropyl cellulose having ahydroxypropyl group content of 53.4 to 77.5% by weight.
 12. The tabletcomposition according to claim 11, wherein the filler is lactose.